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EDITORIAL FOCUS
Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark
MATERNAL-FETAL EXCHANGE OF nutrients and respiratory gases occurs across the brush border of the trophoblast lining the intervillous space of the placenta. The trophoblast is syncytial in nature and has a high rate of turnover. Therefore syncytiotrophoblast is continually replenished from an underlying layer of proliferating stem cells, the villous cytotrophoblasts, often referred to as Langhan's layer (Fig. 1). Syncytiotrophoblast nuclei undergo programmed cell death, and there is strong evidence that the apoptotic cascade is initiated in the villous cytotrophoblast (10, 11). The apoptotic nuclei accumulate near the surface in the "syncytial knots" that are a characteristic of human placenta. From here, they are shed into the maternal circulation. They make a sizeable contribution to the cellular debris of fetal origin that is responsible for the systemic inflammatory response to pregnancy (17). While such a response occurs in normal gestation, it is greatly enhanced in preeclampsia, an endothelial disorder that is a common and potentially dangerous complication of pregnancy. Thus an advance in our comprehension of how these processes are regulated contributes to our understanding both of trophoblast biology and of the causes underlying a major pregnancy disorder. It now appears (5) that trophoblast turnover is regulated, at least in part, by the insulin-like growth factor system.
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While it is clear that birth weight and placental weight are positively correlated with cord blood levels of IGF-I and IGF-II (6, 16), relatively little is known about how the IGF system affects growth of the human placenta. Hitherto, the focus has been on the expression of IGF-II on the extravillous trophoblast that invades the uterine wall and the expression of IGFBP-1 and IGFBP-4 on decidual cells (7, 8, 12). Interaction between IGF-II and IGFBPs at the maternal-fetal interface has been allotted an important role in limiting trophoblast invasion, including the subsequent migration of trophoblast to uterine spiral arteries. Thus it has been suggested that an imbalance in the IGF system leads to restriction of placental and fetal growth through restraining trophoblast invasion and decreasing placental blood flow. In this view, reduced growth of villous trophoblast is seen as secondary to the reduced supply of oxygen and nutrients.
Now a well-designed and carefully executed study by Forbes et al. (5) using first-trimester villous explants convincingly demonstrates a direct effect of the IGF system on trophoblast turnover in human placenta. IGF-I and -II enhanced cytotrophoblast proliferation and syncytium formation and reduced cytotrophoblast apoptosis, suggesting a key role for the IGF system in maintaining the maternal-facing syncytiotrophoblast layer of the placenta. Importantly, IGF applied to this surface, mimicking exposure to maternal IGF-I in the intervillous space, was able to influence proliferation in the underlying cytotrophoblast layer. The effects on proliferation and syncytium formation were shown to be mediated by the MAPK pathway, whereas the effects on survival depended on the phosphoinositide 3-kinase/Akt pathway (5). It is well established that these pathways are activated by binding of IGFs to IGF1R (3), which is expressed on the microvillous membrane of syncytiotrophoblast.
This new study clearly demonstrates the advantage of using villous explants, in which the contact between cellular and syncytial trophoblast is maintained. The two layers are connected by gap junctions (2), and there is likely cell signaling between them. Cytotrophoblast proliferation ceased after the syncytiotrophoblast layer had been removed (5). Regeneration of a continuous layer of syncytiotrophoblast occurred within 4 days, and this process was enhanced by application of IGF-I or IGF-II. This mechanism of tissue damage repair (20) is postulated to involve lateral fusion of a subset of cytotrophoblasts (5). Much previous effort has been expended on trying to understand the biology of trophoblast in primary cell culture and choriocarcinoma cell lines. Primary trophoblasts exit the cell cycle (15), although they subsequently resume mitosis and form syncytia. It needs to be addressed whether this is a process akin to replenishment of syncytiotrophoblast in intact placental villi or, as seems more likely, is related to the separate tissue repair mechanism. There is a clear risk that some conclusions drawn from studies on primary cell culture as well as choriocarcinoma cell lines are misleading. Indeed, there is good reason to subscribe to the authors' view that their results challenge current models of placental development.
There are even implications for the animal models used to study trophoblast turnover. In the guinea pig placenta, maternal blood channels analogous to the intervillous space are lined by syncytiotrophoblast. During the 2-mo gestation period, growth and maintenance of the trophoblast occur from nests of highly proliferative cytotrophoblast (14), much as in human placenta. Fetal growth restriction in guinea pigs is associated with altered expression of components of the IGF system (1). Conversely, exogenous IGF-I and -II stimulate growth of the placental exchange area (19). The guinea pig may be a useful model for studying trophoblast turnover and better than the mouse. In mice, the placental barrier includes three layers of trophoblast, two of them syncytial. Despite considerable progress in understanding cell lineages in murine placenta, the source of the syncytiotrophoblast remains unknown (21). Nor is it clear whether it is replenished during the relatively short life of the murine placenta.
There remains much to be learned with the human villous explant model. Most experiments in the current study were done in 20% oxygen, with just a few controls in 6% oxygen, which is closer to the in vivo levels experienced by trophoblast. The deleterious effect of high oxygen levels on trophoblast ultrastructure has been known for quite some time (22). More recently, it was shown in villous explants that high oxygen levels affect cellular response pathways, including those associated with tissue viability and cell death (18). Future protocols should therefore place greater emphasis on explants cultured at low oxygen tensions.
Trophoblast turnover and renewal need to be tightly regulated to maintain a bilayered structure while permitting the placenta to grow in size. It is now evident that insulin-like growth factors play a key role in promoting this process.
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FOOTNOTES |
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REFERENCES |
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 TOP REFERENCES |
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2. Cronier L, Defamie N, Dupays L, Théveniau-Ruissy M, Goffin F, Pointis G, Malassiné A. Connexin expression and gap junctional intercellular communication in human first trimester trophoblast. Mol Hum Reprod 8: 1005–1013, 2002.
3. Dupont J, Dunn SE, Barrett JC, LeRoith D. Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression. Recent Prog Horm Res 58: 325–342, 2003.
4. Efstratiadis A. Genetics of mouse growth. Int J Dev Biol 42: 955–976, 1998.[Web of Science][Medline]
5. Forbes K, Westwood M, Baker PN, Aplin JD. Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta. Am J Physiol Cell Physiol (April 9, 2008). doi:10.1152/ ajpcell.00035.2008.
6. Giudice LC, de Zegher F, Gargosky SE, Dsupin BA, de las Fuentes L, Crystal RA, Hintz RL, Rosenfeld RG. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 80: 1548–1555, 1995.
7. Giudice LC, Conover CA, Bale L, Faessen GH, Ilg K, Sun I, Imani B, Suen LF, Irwin JC, Christiansen M, Overgaard MT, Oxvig C. Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation. J Clin Endocrinol Metab 87: 2359–2366, 2002.
8. Han VK, Bassett N, Walton J, Challis JR. The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab 81: 2680–2693, 1996.[Abstract]
9. Han VK, Carter AM. Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animals. Placenta 21: 289–305, 2000.[CrossRef][Web of Science][Medline]
10. Huppertz B, Frank HG, Reister F, Kingdom J, Korr H, Kaufmann P. Apoptosis cascade progresses during turnover of human trophoblast: analysis of villous cytotrophoblast and syncytial fragments in vitro. Lab Invest 79: 1687–1702, 1999.[Web of Science][Medline]
11. Huppertz B, Frank HG, Kaufmann P. The apoptosis cascade–morphological and immunohistochemical methods for its visualization. Anat Embryol (Berl) 200: 1–18, 1999.[CrossRef][Medline]
12. Lathi RB, Hess AP, Tulac S, Nayak NR, Conti M, Giudice LC. Dose-dependent insulin regulation of insulin-like growth factor binding protein-1 in human endometrial stromal cells is mediated by distinct signaling pathways. J Clin Endocrinol Metab 90: 1599–1606, 2005.
13. Martina NA, Kim E, Chitkara U, Wathen NC, Chard T, Giudice LC. Gestational age-dependent expression of insulin-like growth factor-binding protein-1 (IGFBP-1) phosphoisoforms in human extraembryonic cavities, maternal serum, and decidua suggests decidua as the primary source of IGFBP-1 in these fluids during early pregnancy. J Clin Endocrinol Metab 82: 1894–1898, 1997.
14. Mess A. The guinea pig placenta: model of placental growth dynamics. Placenta 28: 812–815, 2007.[CrossRef][Web of Science][Medline]
15. Morrish DW, Dakour J, Li H, Xiao J, Miller R, Sherburne R, Berdan RC, Guilbert LJ. In vitro cultured human term cytotrophoblast: a model for normal primary epithelial cells demonstrating a spontaneous differentiation programme that requires EGF for extensive development of syncytium. Placenta 18: 577–585, 1997.[Web of Science][Medline]
16. Ong K, Kratzsch J, Kiess W, Costello M, Scott C, Dunger D. Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. The ALSPAC Study Team Avon Longitudinal Study of Pregnancy and Childhood. J Clin Endocrinol Metab 85: 4266–4269, 2000.
17. Redman CW, Sargent IL. Microparticles and immunomodulation in pregnancy and pre-eclampsia. J Reprod Immunol 76: 61–67, 2007.[CrossRef][Web of Science][Medline]
18. Reti NG, Lappas M, Huppertz B, Riley C, Wlodek ME, Henschke P, Permezel M, Rice GE. Effect of high oxygen on placental function in short-term explant cultures. Cell Tissue Res 328: 607–616, 2007.[CrossRef][Web of Science][Medline]
19. Sferruzzi-Perri AN, Owens JA, Pringle KG, Robinson JS, Roberts CT. Maternal insulin-like growth factors-I and -II act via different pathways to promote fetal growth. Endocrinology 147: 3344–3355, 2006.
20. Simán CM, Sibley CP, Jones CJ, Turner MA, Greenwood SL. The functional regeneration of syncytiotrophoblast in cultured explants of term placenta. Am J Physiol Regul Integr Comp Physiol 280: R1116–R1122, 2001.
21. Simmons DG, Fortier AL, Cross JC. Diverse subtypes and developmental origins of trophoblast giant cells in the mouse placenta. Dev Biol 304: 567–578, 2007.[CrossRef][Web of Science][Medline]
22. Watson AL, Skepper JN, Jauniaux E, Burton GJ. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab 83: 1697–1705, 1998.
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